Repeated drug injections lead to sensitization of their stimulant effects in mice, a phenomenon sometimes referred to as drug psychomotor sensitization. Previous studies showed that sensitization to ... [more ▼]

Repeated drug injections lead to sensitization of their stimulant effects in mice, a phenomenon sometimes referred to as drug psychomotor sensitization. Previous studies showed that sensitization to cocaine is context dependent as its expression is reduced in an environment that was not paired with cocaine administration. In contrast, the effects of the test context on ethanol sensitization remain unclear. In the present study, female OF1 mice were repeatedly injected with 1.5 g/kg ethanol to test for both the effects of context novelty/familiarity and association on ethanol sensitization. A first group of mice was extensively pre-exposed to the test context before ethanol sensitization and ethanol injections were paired with the test context (familiar and paired group). A second group was not pre-exposed to the test context, but ethanol injections were paired with the test context (nonfamiliar and paired group). Finally, a third group of mice was not pre-exposed to the test context and ethanol was repeatedly injected in the home cage (unpaired group). Control groups were similarly exposed to the test context, but were injected with saline. In a second experiment, cocaine was used as a positive control. The same behavioral procedure was used, except that mice were injected with 10 mg/kg cocaine instead of ethanol. The results show a differential involvement of the test context in the sensitization to ethanol and cocaine. Cocaine sensitization is strongly context dependent and is not expressed in the unpaired group. In contrast, the expression of ethanol sensitization is independent of the context in which it was administered, but is strongly affected by the relative novelty/familiarity of the environment. Extensive pre-exposure to the test context prevented the expression of ethanol sensitization. One possible explanation is that expression of ethanol sensitization requires an arousing environment. [less ▲]

Repeated ethanol injections lead to a sensitization of its stimulant effects in mice. Some recent results argue against a role for ventral tegmental area (VTA) dopamine neurons in ethanol behavioral ... [more ▼]

Repeated ethanol injections lead to a sensitization of its stimulant effects in mice. Some recent results argue against a role for ventral tegmental area (VTA) dopamine neurons in ethanol behavioral sensitization. The aim of the present study was to test whether in vivo ethanol locomotor sensitization correlates with changes in either basal- or ethanol evoked firing rates of dopamine neurons in vitro. Female Swiss mice were daily injected with 2.5 g/kg ethanol (or saline in the control group) for 7 days and their locomotor activity was recorded. At the end of the sensitization procedure, extracellular recordings were made from dopaminergic neurons in midbrain slices from these mice. Significantly higher spontaneous basal firing rates of dopamine neurons were recorded in ethanol-sensitized mice relative to control mice, but without correlations with the behavioral effects. The superfusion of sulpiride, a dopamine D2 antagonist, induced a stronger increase of dopamine neuron firing rates in ethanol-sensitized mice. This shows that the D2 feedback in dopamine neurons is preserved after chronic ethanol administration and argues against a reduced D2 feedback as an explanation for the increased dopamine neuron basal firing rates in ethanol-sensitized mice. Finally, ethanol superfusion (10–100 mM) significantly increased the firing rates of dopamine neurons and this effect was of higher magnitude in ethanol-sensitized mice. Furthermore, there were significant correlations between such a sensitization of dopamine neuron activity and ethanol behavioral sensitization. These results support the hypothesis that changes in brain dopamine neuron activity contribute to the behavioral sensitization of the stimulant effects of ethanol. [less ▲]

Rationale: In humans, novelty/sensation seeking is seen as a personality trait with a positive relationship with addiction vulnerability. In animal studies, one of the standard proce-dures to model ... [more ▼]

Rationale: In humans, novelty/sensation seeking is seen as a personality trait with a positive relationship with addiction vulnerability. In animal studies, one of the standard proce-dures to model novelty seeking is the "response to novelty," i.e., the levels of locomotor activity in a new environment. In rodents, a positive correlation was demonstrated between the response to novelty and several effects of drugs, especially the locomotor stimulant effects of cocaine. Objectives: The present study was designed to test in mice whether the response to novelty is stable across environments and whether its relationship with the stimulant effects of cocaine is altered by environmental changes. Experiment 1 assessed the responses to novelty of the same mice in two different novel environments. Experiment 2 tested the correlation between response to novelty and acute stimulant effects of cocaine recorded in two distinct environments. Results: The results show a weak correlation only during the first 5 min of the session between the responses to novelty measured in two distinct environments. Experiment 2 demonstrates that novelty responses and stimulant effects of cocaine are positively correlated only when both behavioral responses are measured in the same environment. In contrast, the relationship between response to novelty and acute stimulant effects of cocaine is completely lost when the behavioral responses are recorded in two different environments. Conclusions: The present results question the usual interpretation of the correlation between the response to novelty and the stimulant effects of cocaine as reflecting a relationship between two underlying individual stable characteristics. [less ▲]

Rationale. Due to their maturing brain, adolescents are suggested to be more vulnerable to the long-term consequences of chronic alcohol use. Increased sensitization to the stimulant effects of ethanol is ... [more ▼]

Rationale. Due to their maturing brain, adolescents are suggested to be more vulnerable to the long-term consequences of chronic alcohol use. Increased sensitization to the stimulant effects of ethanol is a possible consequence of ethanol exposure during adolescence. Objectives. The aim of this study was to characterize the long-term alterations in the stimulant effects of ethanol and in the rate of ethanol sensitization in mice pre-exposed to ethanol during adolescence in comparison to mice pre-exposed to ethanol in adulthood. Methods. Adolescent and adult female SWISS mice were injected with saline or ethanol (2.5 or 4 g/kg) during 14 consecutive days. After a three weeks period of ethanol abstinence, mice were tested as adults before and after a second exposure to daily repeated ethanol injections. Results. All mice pre-exposed to ethanol as adults or adolescents showed higher stimulant effects when re-exposed to ethanol three weeks later. However, this enhanced sensitivity to the stimulant effects of ethanol was of significantly higher magnitude in mice repeatedly injected with high ethanol doses (4g/kg) during adolescence. Furthermore, the increased expression of ethanol stimulant effects in these mice was maintained even after a second procedure of ethanol sensitization. Conclusions. Adolescence is a critical period for the development of a sensitization to ethanol stimulant properties providing that high intermittent ethanol doses are administered. These results might contribute to explain the relationship between age at first alcohol use and risks of later alcohol problems and highlight the dangers of repeated consumption of high alcohol amounts in young adolescents. [less ▲]

The adolescent brain has been suggested to be particularly sensitive to ethanol-induced neuroadaptations, which in turn could increase the risk of youths for alcohol abuse and dependence. Sensitization to ... [more ▼]

The adolescent brain has been suggested to be particularly sensitive to ethanol-induced neuroadaptations, which in turn could increase the risk of youths for alcohol abuse and dependence. Sensitization to the locomotor stimulant effects of ethanol has often been used as an animal model of ethanol-induced neuroadaptations. Previously, we showed that young mice were more sensitive than adults to the locomotor sensitization induced by high ethanol doses. However, this effect could be due to age-related differences in chronic tolerance to the sedative effects of ethanol. The aim of the present study is to assess chronic tolerance to the sedative effects of ethanol in weaning 21-day-old (P21), adolescent 35-day-old (P35) and adult 63-day-old (P63) female Swiss mice. After a daily injection of saline or 4 g/kg ethanol during 6 consecutive days, all P21, P35 and P63 mice were injected with 4 g/kg ethanol and submitted to the loss of righting reflex procedure. Our results confirm that the sensitivity to the acute sedative effects of ethanol gradually increases with age. Although this schedule of ethanol injections induces significant age-related differences in ethanol sensitization, it did not reveal significant differences between P21, P35 and P63 mice in the development of a chronic ethanol tolerance to its sedative effects. The present results show that age-related differences in the development of ethanol sensitization cannot be explained by differences in chronic ethanol tolerance to its sedative effects. More broadly, they do not support the idea that ethanol-induced sensitization is a by-product of chronic ethanol tolerance. [less ▲]

Alcohol exposure during early adolescence is believed to durably alter the behavioral properties of ethanol, increasing the likelihood of later alcohol-related disorders. The aim of the present ... [more ▼]

Alcohol exposure during early adolescence is believed to durably alter the behavioral properties of ethanol, increasing the likelihood of later alcohol-related disorders. The aim of the present experiments was to characterize changes in the behavioral effects of ethanol in adult female Swiss mice after a chronic ethanol exposure during adolescence, extending from postnatal day 28 to postnatal day 42. After a chronic ethanol exposure during adolescence (daily injections of 0, 2.5 or 4 g/kg ethanol for 14 consecutive days), adult mice were tested at postnatal day 63. The locomotor stimulant effects of ethanol, together with ethanol sensitization were tested in experiment 1. In experiment 2, the sedative effects of ethanol were assessed with the loss of righting reflex procedure. Finally, in experiment 3, the anxiolytic effects of ethanol were tested with the light/dark box test. Adult mice chronically exposed to ethanol during adolescence showed a lower basal locomotor activity, but higher locomotor stimulant effects of ethanol than non-exposed mice. Additionally, these adult mice developed higher rates of ethanol sensitization after chronic re-exposure to ethanol in adulthood. Adult mice exposed to ethanol during adolescence also had a stronger tolerance to the sedative effects of high ethanol doses, although they showed no evidence of changes in the anxiolytic effects of ethanol. These results are in agreement with the thesis that chronic alcohol consumption during adolescence, especially in high amounts, increases the risk of later alcohol-related disorders. [less ▲]

Rationale: The maturing adolescent brain has been suggested to be more sensitive than the adult brain to ethanol-induced neuroadaptations. In animal studies, sensitization to the stimulant effects of ... [more ▼]

Rationale: The maturing adolescent brain has been suggested to be more sensitive than the adult brain to ethanol-induced neuroadaptations. In animal studies, sensitization to the stimulant effects of ethanol is used to study the vulnerability to chronic ethanol-induced neurobehavioral alterations. Objectives: The aim of the present study was to systematically characterize age-dependent changes in the development and expression of the sensitization to the stimulant effects of a range of ethanol doses in female Swiss mice. Three ages were studied: 21-day-old mice (postweanlings), 35-day-old mice (adolescents), and 63-day-old mice (adults). Methods: Postweanling, adolescent, and adult mice were daily injected with saline or various ethanol doses (1.5 to 4 g/kg) for 7 days. They were then tested for acute and sensitized locomotor activity. Results: Postweanling and adolescent mice were more sensitive than adult mice to the acute stimulant effects of ethanol. In adult mice, daily injections of ethanol at doses between 2.5 and 4 g/kg led to significant sensitization. Higher ethanol doses (3.5 and 4 g/kg) were required to induce sensitization in postweanling and adolescent mice. However, younger mice showed ethanol sensitization of higher magnitude. Conclusions: Young mice develop very strong ethanol sensitization at doses that mimic binge drinking in humans. These results might explain why early ethanol drinking during adolescence is related to a higher prevalence of subsequent alcohol disorders. [less ▲]

The adolescent period is characterized by behavioral and neurobiological changes, which might predispose adolescents to the long-term negative consequences of alcohol. For example, enhanced risks of ... [more ▼]

The adolescent period is characterized by behavioral and neurobiological changes, which might predispose adolescents to the long-term negative consequences of alcohol. For example, enhanced risks of alcohol dependence are reported when drinking is initiated early. In the present studies, we used Swiss female mice to test whether chronic ethanol injections during adolescence durably affect the sensitivity to the stimulant effects of ethanol in adulthood. In a first set of experiments, several groups of young (28 day-old) mice were daily injected with various ethanol doses (1.5 – 4 g/kg) to test for ethanol sensitization during adolescence in comparison to adult mice exposed to the same schedule of ethanol injections. The results show that young mice express much higher stimulant effects after acute ethanol injections. However, they also require higher ethanol doses than adult mice to develop a sensitization to the stimulant effects of ethanol. In a second set of experiments, 28 day-old mice were sensitized to ethanol for 14 days with high ethanol doses (2.5 or 4 g/kg) and then tested for the stimulant effects of ethanol and the development of ethanol sensitization in adulthood. The results of this second set of experiments show that mice sensitized to ethanol during their adolescence remain more sensitive to the acute stimulant effects of ethanol in adulthood, especially when high ethanol doses were administered. However, the rate of the development of a sensitization to this effect was only slightly affected relative to adult mice exposed to a chronic ethanol regimen for the first time. Together, these results indicate that adolescent mice are more sensitive to the stimulant effects of ethanol but require higher ethanol doses to develop a sensitization. However, when a sensitization develops during adolescence, these mice still experience higher ethanol stimulant effects when tested in adulthood. [less ▲]

Rationale: The adolescent period is characterized by a specific sensitivity to the effects of alcohol, which is believed to contribute to the enhanced risks of alcohol dependence when drinking is ... [more ▼]

Rationale: The adolescent period is characterized by a specific sensitivity to the effects of alcohol, which is believed to contribute to the enhanced risks of alcohol dependence when drinking is initiated early during adolescence. In adolescent rodents, while the reduced sensitivity to the sedative effects of ethanol has been well characterized, its stimulant effects have not yet been extensively studied. Objectives: The present study characterized the development of the stimulant and sedative effects of acute ethanol in male and female Swiss mice from weaning to early adulthood and tested whether both effects are interrelated. Methods: In a first experiment, mice aged 21, 28, 35, 42 and 60 days were injected with various ethanol doses and tested for ethanol-induced locomotor activity. In an independent experiment, mice of the same groups of age were injected with 4 g/kg ethanol and ethanol-induced sedation was quantified with the loss of righting reflex procedure. Results: In male and female mice, the stimulant effects of ethanol gradually decreased, whereas its sedative effects increased with age. When the sedation was statistically controlled using a covariance analysis, the differences between adult and juvenile mice in the locomotor stimulation were significantly reduced. Conclusions: From weaning to early adulthood, the acute stimulant and sedative effects of ethanol show gradual changes that are similar in male and female mice. Although the initial tolerance to the sedative effects of ethanol contribute to the changes in ethanol-induced locomotor activity, young mice also show a higher sensitivity to the stimulant effects of ethanol. [less ▲]

BACKGROUND: Acetaldehyde, the first metabolite of ethanol, has been suggested to be involved in many behavioral effects of ethanol. However, few studies have investigated the hypothermic effects of ... [more ▼]

BACKGROUND: Acetaldehyde, the first metabolite of ethanol, has been suggested to be involved in many behavioral effects of ethanol. However, few studies have investigated the hypothermic effects of acetaldehyde or the contribution of acetaldehyde to ethanol-induced hypothermia. The aim of the present study is to better understand the hypothermic effects of acetaldehyde and the possible contribution of acetaldehyde in ethanol-induced hypothermia, especially under conditions leading to acetaldehyde accumulation. METHODS: Female Swiss mice were injected intraperitoneally with ethanol and acetaldehyde and their rectal temperatures were measured with a digital thermometer at various time points after the injections. Experiment 1 compared the hypothermic effects of various acetaldehyde doses (0 to 300 mg/kg) with a reference dose of ethanol (3 g/kg). Experiment 2 tested the effects of a pretreatment with the aldehyde dehydrogenase (ALDH) inhibitor cyanamide (25 mg/kg) on ethanol- and acetaldehyde-induced hypothermia. In experiments 3 and 4, mice received a combined pretreatment with cyanamide and the alcohol dehydrogenase (ADH) inhibitor 4-Methylpyrazole (10 mg/kg) before the injection of ethanol or acetaldehyde. RESULTS: Acetaldehyde at doses between 100 and 300 mg/kg induced significant hypothermic effects, but of shorter duration than ethanol-induced hypothermia. The inhibition of ALDH enzymes by cyanamide induced a strong potentiation of both ethanol- and acetaldehyde-induced hypothermia. The pretreatment with 4-MP prevented the potentiation of ethanol-induced hypothermia by cyanamide, but slightly increased the potentiation of acetaldehyde-induced hypothermia by cyanamide. CONCLUSIONS: The results of the present study clearly show that acetaldehyde has hypothermic properties in mice at least at relatively high concentrations. Furthermore, the accumulation of acetaldehyde following ALDH inhibition strongly enhanced the hypothermic effects of ethanol. These latter results confirm the hypothermic properties of acetaldehyde and show that acetate, the next step in ethanol metabolism, is not involved in these hypothermic effects. Finally, the experiment with 4-MP indicates that the potentiating effects of cyanamide are mediated by the peripheral accumulation of acetaldehyde, which then reaches the brain to induce a severe hypothermia. [less ▲]

Whereas human studies keep reporting evidence that acetaldehyde accumulation prevents alcohol drinking and alcoholism, animal studies support a rewarding rather than aversive role for acetaldehyde. In ... [more ▼]

Whereas human studies keep reporting evidence that acetaldehyde accumulation prevents alcohol drinking and alcoholism, animal studies support a rewarding rather than aversive role for acetaldehyde. In recent years, the reinforcing properties of acetaldehyde were demonstrated in various rodent strains and using different experimental methods. These results led to the hypothesis that acetaldehyde might be involved in the addictive properties of alcohol. In addition to its possible role in the reinforcing properties of alcohol, there is also evidence that acetaldehyde is involved in many other behavioral effects of ethanol. Using various behavioral procedures with both mice and rats, we have studied the behavioral effects of direct acetaldehyde injections. Additionally, in independent experiments we have compared the effects of ethanol in mice with or without a pre-treatment with the aldehyde dehydrogenase inhibitor cyanamide, which produces acetaldehyde accumulation. The results of these studies show that acetaldehyde produces a wide spectrum of behavioral effects, including reinforcement, aversion, sedation, ataxia and amnesia. These effects were mainly dependent upon acetaldehyde doses, with some of them showing an inverted U shape dose-response curve. These results also suggest that acetaldehyde might mediate or contribute to many of the behavioral effects of ethanol and especially to alcohol abuse and alcoholism. [less ▲]

RATIONALE: Repeated administrations of ethanol induce a progressive and enduring increase in its locomotor stimulant effects, a phenomenon termed behavioral sensitization that has not been systematically ... [more ▼]

RATIONALE: Repeated administrations of ethanol induce a progressive and enduring increase in its locomotor stimulant effects, a phenomenon termed behavioral sensitization that has not been systematically characterized. OBJECTIVE: The aim of the present studies was to characterize the development and expression of ethanol sensitization in female Swiss mice by examining (1) the doses of ethanol that induce behavioral sensitization, (2) the doses of acute ethanol challenges that are necessary to express behavioral sensitization, (3) the effects of the intervals between administrations, and (4) the context dependency of ethanol sensitization. MATERIALS AND METHODS: Mice were i.p. injected for 8 days with various ethanol doses, and locomotion was recorded for 5 min. Two days after the last sensitization session, ethanol sensitization was tested in 30-min test sessions. RESULTS: Mice repeatedly injected with 2.5 g/kg ethanol showed a progressive (200-300%) increase in locomotor activity. In response to a 2.5 g/kg ethanol challenge, the mice repeatedly treated with doses above 1.5 g/kg showed a significant sensitization. Following the induction of sensitization with the maximally effective sensitizing dose (2.5 g/kg), mice showed greater activation after challenges with 1.5, 2.0, 2.5, and 3.0 g/kg ethanol. The intervals (24, 48, or 96 h) between ethanol injections did not affect the induction or expression of sensitization. Finally, sensitization to 2.5 g/kg ethanol was expressed regardless of the context in which it was induced. CONCLUSIONS: Female Swiss mice develop a robust context-independent sensitization after repeated ethanol injections at all doses above 1.5 g/kg, including highly sedative doses such as 4 g/kg. [less ▲]

Acetaldehyde has been postulated to mediate several of the behavioral effects of ethanol, including its reinforcing properties. At the highest doses, alcohol disrupts the acquisition and performance of ... [more ▼]

Acetaldehyde has been postulated to mediate several of the behavioral effects of ethanol, including its reinforcing properties. At the highest doses, alcohol disrupts the acquisition and performance of memory tasks, culminating with the blackout experience at high blood alcohol concentrations. However, it remains unknown whether acetaldehyde is involved in such memory impairments induced by acute ethanol. Additionally, chronic alcohol consumption in humans sometimes leads to persistent memory impairments partly due to serious brain damages. The Wernicke-Korsakoff syndrome, characterized by severe anterograde amnesia, is the most serious memory disorder induced by chronic alcohol. The aim of the present study was to show whether acute and chronic treatments with acetaldehyde, the first metabolite of ethanol, lead to similar memory impairments as ethanol in mice. Memory performances of Swiss and C57BL/6J mice were tested in both the passive avoidance task and the fear conditioning procedure. In the first part of the experiments mice were injected with acute acetaldehyde (50 to 300 mg/kg) immediately after the training phase. In the second part of the experiment, mice were tested for memory performance after 10 daily acetaldehyde injections. The first part of the experiments shows that acute acetaldehyde administrations produce a strong amnesic effect in both experimental paradigms. Additionally, the amnesic effects of acetaldehyde were more consistent than those observed after ethanol administration. In the second part of the studies, we show that 10 daily acetaldehyde injections to mice led to a severe and persistent anterograde amnesia in both the pavlovian and the operant learning tasks. In conclusion, acute acetaldehyde produces strong amnesic effects trough yet unknown pharmacological mechanisms. In addition, chronic acetaldehyde administration leads to persistent memory impairments. These results suggest that acetaldehyde might be involved in both the acute amnesic effects of high ethanol doses and the neurotoxic effects of chronic alcohol consumption. [less ▲]

Several studies have suggested that acetaldehyde, the first product of ethanol metabolism, is involved in the locomotor stimulant effects of ethanol in mice, although it has never been formally tested ... [more ▼]

Several studies have suggested that acetaldehyde, the first product of ethanol metabolism, is involved in the locomotor stimulant effects of ethanol in mice, although it has never been formally tested whether acetaldehyde injected directly into the brain of mice has stimulant properties. Recently, it was also shown in rats that both ethanol and acetaldehyde can induce opposite locomotor effects according to the route of administration. Whereas peripheral administrations of ethanol and acetaldehyde induced locomotor depressant effects, their infusions directly into the brain produced locomotor stimulation. The aim of the present study was to characterize in mice the locomotor effects of ethanol and acetaldehyde injected either peripherally by the intraperitoneal route or centrally into the brain ventricles. Additionally, the effects of ethanol and acetaldehyde were compared in two strains of mice known for their differential sensitivity to the locomotor effects of ethanol, namely Swiss and C57BL/6J mice. Ethanol induced a biphasic effect on locomotor activity in Swiss mice, with stimulant effects at low to moderate doses and depressant effects at higher doses. Such a profile of effects was observed whatever the route of administration, peripheral or central. In C57BL/6J mice, ethanol only induced monophasic depressant effects. In this mouse strain, no evidence of the stimulant effects of ethanol was found after either an i.p. or an i.c.v. administration of ethanol. In contrast to ethanol, acetaldehyde yielded only depressant effects in both strains of mice after both peripheral and central administrations. These results indicate that the route of administration does not alter the locomotor effects of ethanol and acetaldehyde in mice. Additionally, the present study shows that the stimulant properties of acetaldehyde, even after direct infusion into the brain, are not as obvious as previously speculated. [less ▲]

in Alcohol Research & Health : The Journal of the National Institute on Alcohol Abuse & Alcoholism (2006), 29(4), 258-265

Acetaldehyde is the first active breakdown product (i.e., metabolite) generated during alcohol metabolism. It has toxic properties but also exerts other actions on the body (i.e., has pharmacological ... [more ▼]

Acetaldehyde is the first active breakdown product (i.e., metabolite) generated during alcohol metabolism. It has toxic properties but also exerts other actions on the body (i.e., has pharmacological properties). Recent studies have shown that the direct administration of acetaldehyde, especially into the brain, induces several effects that mimic those of alcohol. High doses of acetaldehyde induce sedative as well as movement-and memory-impairing effects, whereas lower doses produce behavioral effects (e.g., stimulation and reinforcement) that are characteristic of addictive drugs. When acetaldehyde accumulates outside the brain (i.e., in the periphery), adverse effects predominate and prevent further alcohol drinking. To investigate the role of acetaldehyde in mediating alcohol's effects, investigators have pharmacologically manipulated alcohol metabolism and the production of acetaidehyde within the body (i.e., endogenous acetaldehyde production). Studies manipulating the activity of the enzyme catalase, which promotes acetaldehyde production in the brain, suggest that acetaldehyde contributes to many behavioral effects of alcohol, especially its stimulant properties. However, it remains controversial whether acetaldehyde concentrations obtained under normal physiological conditions are sufficient to induce significant pharmacological effects. Current evidence suggests that the contribution of acetaldehyde to alcohol's effects is best explained by a process in which acetaidehyde modulates, rather than mediates, some of alcohol's effects. [less ▲]